Alzheimer?s disease (AD) is defined neuropathologically by extracellular plaques composed of ?-amyloid (A?42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. A? accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose comprehensive in vitro analysis of a unique set of novel small molecule drugs known gamma- secretase modulators (GSMs) to further explore AD therapeutics. This proposal will focus on testing an optimal lead clinical candidate for efficacy in human neurons aimed at halting A?42- related pathologies AD. Our overarching hypothesis is GSM therapy aimed to disrupt production of A?42 will be an efficacious treatment approach for prodromal or early AD, as well as sporadic late-onset AD. The goal of this project is to validate target engagement in human neurons from selected patients.